B. Tech. (Department of Biotechnology, Faculty of Applied and Computer Sciences), Vaal University of Technology. / Background: In a group of the elderlies (older person) in Sharpeville, Gauteng, South Africa, the majority live in poverty with a poor nutritional status. This makes them susceptible to develop infectious diseases as well as the risk of Chronic Diseases of the Lifestyle (CDL) such as cancer, diabetes, heart attack, obesity and hypertension. One of the most constant features of aging is the progressively elevated levels of coagulation factors such as FVII, fibrinogen, and impairment of fibrinolysis might play a role in the ageing process. These are associated with increased susceptibility to Cardiovascular diseases (CVD) commonly found. An association between elevated levels of FVII and R353Q polymorphism has been established as a risk factor for CVD. This genetic polymorphism R353Q characterizes the substitution in the exon 8 of the FVII gene of guanine-to-adenine, which results in the replacement of arginine (R) by glutamine (Q) in codon 353 of the F7gene. Objectives: The aim of this study was to evaluate the prevalence of R353Q polymorphism in correlation with haemostatic markers within an urban elderly community in South Africa. Method: This study was ethically approved, and it is an experimental research design on the prevalence of R353Q polymorphism in correlation with homeostatic status (Factor VII, Fibrinogen and PAI-1). The study was done in a black elderly population living in the Vaal triangle region of Sharpeville, attending a day care center, who gave consent to participate in the study. A purposely selected sample of 102 subjects, who met the inclusion criteria were used. The homeostatic status was measured by factor VII and fibrinogen measuring coagulation and PAI-1 measuring fibrinolysis. Results: The prevalence of R353Q genetic polymorphism was established in 14.5% of the sampled population. The prevalence of the RQ (AG) genotype was determined in the sample population with 6.5 % of elevated factor VII levels, 7.8% of increased fibrinogen levels (coagulation) and 10.5 % of decreased levels of PAI-1. The R(A) allele, was detected in 1.3% of the sampled population of normal levels of FVII, fibrinogen and PAI-1. The dominant allele G(Q) was present in 76.3% of the sampled population. An imbalance haemostatic marker was established in the sampled population with 61% of elevated levels of factor VII, 70% of elevated levels of fibrinogen and 88% had a decreased level of PAI-1. Conclusion: The prevalence of R353Q polymorphism was established in this sample population, having an imbalanced haemostatic status of hypercoagulation (factor VII and fibrinogen) and imbalance fibrinolysis (PAI-1), which are strongly associated to CVDs.

Motivation - Depression is a mental disorder that has been associated with cardiovascular morbidity and mortality in the Western world. Cardiometablic mechanisms have been implicated as possible intermediating factors in the relationship between depressive symptoms and cardiovascular disease; however this has not yet been determined in black Africans (hereafter referred to as Africans). Aim - The overarching aim of this study was to investigate the relationship between depressive symptoms and cardiometabolic risk. We therefore aimed to assess cardiometabolic function, neuroendocrine responses, inflammatory and haemostatic markers in Africans with depressive symptoms compared to those without symptoms of depression. Methodology - Manuscripts presented in Chapter 2, 3 and 4 utilised data from the cross-sectional, target population multi-disciplinary “Sympathetic activity and Ambulatory Blood Pressure in Africans” (SABPA) study. The participants comprised of 200 African teachers from the Dr Kenneth Kaunda District in North-West province, South Africa. As cardiovascular disease is compromised by a positive HIV status, 19 participants were excluded from further statistical analysis. Stratification was based on the Patient Health Questionnaire 9-item (PHQ-9), which has been validated in a sub-Saharan African setting. PHQ-9 scores > 10 were used to classify participants as having signs of depressive symptoms. Subjects were further stratified by gender (Manuscript 1 and 3) and cortisol responses (Manuscript 2). Cardiometabolic health measures included 24-hour blood pressure, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], left ventricular hypertrophy (LVH),inflammatory and haemostatic markers (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Resting 12-lead ECG Cornell Product-Left ventricular hypertrophy (CP-LVH) was measured as a marker of target end-organ damage and cardiovascular dysfunction (Manuscript 1 and 2). Means and prevalence were computed through t-test and Chi-square analysis respectively. Significant differences of mean cardiometabolic measures between depressive symptom status groups were also determined by analysis of covariance (adjusted for traditional cardiovascular risk factors and additional factors as specific per manuscript). Multivariate analysis was used to demonstrate associations between left ventricular hypertrophy (LVH) and cardiometabolic markers in Africans with depressive symptoms (Manuscript 1 and 2) and a logistic regression analysis were performed to examine the association between depressive symptoms and inflammatory/haemostatic factors (Manuscript 3). All subjects who participated gave informed consent, the study was approved by the Ethics Committee of North-West University (NWU-0003607S6), in accordance with the principles outlined by the World Medical Association Declaration of Helsinki of 1975 (revised 2008). Results and conclusions of the individual manuscripts - The aim of the study was to investigate the associations between depressive symptoms and cardiometabolic function including cardiovascular dysfunction. Markers of cardiometabolic function assessed were 24 hour blood pressure measurements, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], inflammatory and haemostatic variables (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Manuscript 1, focused on LVH as a marker of cardiovascular dysfunction and metabolic syndrome components as markers of cardiometabolic function. The aim of the study was to assess the associations between LVH and metabolic syndrome (MetS) risk markers in participants with and without depressive symptoms. Results revealed that in African men with depressive symptoms the most significant determinants of LVH were systolic blood pressure (SBP) and the percentage glycosylated haemoglobin (HbA1c). While in African women (with depressive symptoms), this association was determined by low high-density lipoprotein (HDL-cholesterol). The study concluded that in black African men, independent of depressive symptoms, cardiometabolic factors (namely SBP and HbA1c) may be the driving significant factors in the development of cardiovascular diseases. Furthermore, the data showed that depressive symptoms in African women were associated with a measure of target end organ damage, and that this association was driven by a metabolic factor. Manuscript 2, the aim of this manuscript was to examine the relationship between depressive symptoms, neuroendocrine responses [with cortisol and 3-methoxy-phenylglycol (MHPG) as markers] and cardiovascular risk, i.e. LVH. The results revealed that Africans with depressive symptoms demonstrated blunted cortisol and MHPG levels in response to acute mental stress, in comparison to those without symptoms of depression. Additionally, these low cortisol and blunted MHPG responses were associated with LVH in this ethnic group. The conclusion for this manuscript was that, blunted neuroendocrine responses linked depressive symptoms and ECG left ventricular hypertrophy in Africans. When coupled to their hypertensive status, these vasoconstrictive responses (cortisol and MHPG) may underpin the increased long-term depression and vascular disease risk in urban Africans. Manuscript 3, the aim of this manuscript was to investigate the relationship between depressive symptoms and inflammatory/haemostatic markers in a cohort of urban-dwelling black African men and women. Our data demonstrated hypercoagulation vulnerability in African men with depressive symptoms. The African men with signs of depression displayed higher plasminogen activator inhibitor (PAI-1) levels and marginally elevated D-dimer levels. It was concluded that hypercoagulation may partially be the mediating factor between depressive symptoms and cardiovascular risk in African men; a situation that may be exacerbated by hyperkinetic blood pressure. In conclusion, through the assessement of cardiometabolic function and neuroendocrine responses, it seems that Africans withdepressive symptoms are at great risk for cardiovascular related morbidity and mortality, this was particulary evident in the African men (Manuscript 1 and 3). Additionally, it appears that blunted neuroendocrine responses and hypercoagulation could be seen as possible cardiovascular risk markers in Africans with depressive symptoms. / PhD (Physiology), North-West University, Potchefstroom Campus, 2014

Motivation - Depression is a mental disorder that has been associated with cardiovascular morbidity and mortality in the Western world. Cardiometablic mechanisms have been implicated as possible intermediating factors in the relationship between depressive symptoms and cardiovascular disease; however this has not yet been determined in black Africans (hereafter referred to as Africans). Aim - The overarching aim of this study was to investigate the relationship between depressive symptoms and cardiometabolic risk. We therefore aimed to assess cardiometabolic function, neuroendocrine responses, inflammatory and haemostatic markers in Africans with depressive symptoms compared to those without symptoms of depression. Methodology - Manuscripts presented in Chapter 2, 3 and 4 utilised data from the cross-sectional, target population multi-disciplinary “Sympathetic activity and Ambulatory Blood Pressure in Africans” (SABPA) study. The participants comprised of 200 African teachers from the Dr Kenneth Kaunda District in North-West province, South Africa. As cardiovascular disease is compromised by a positive HIV status, 19 participants were excluded from further statistical analysis. Stratification was based on the Patient Health Questionnaire 9-item (PHQ-9), which has been validated in a sub-Saharan African setting. PHQ-9 scores > 10 were used to classify participants as having signs of depressive symptoms. Subjects were further stratified by gender (Manuscript 1 and 3) and cortisol responses (Manuscript 2). Cardiometabolic health measures included 24-hour blood pressure, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], left ventricular hypertrophy (LVH),inflammatory and haemostatic markers (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Resting 12-lead ECG Cornell Product-Left ventricular hypertrophy (CP-LVH) was measured as a marker of target end-organ damage and cardiovascular dysfunction (Manuscript 1 and 2). Means and prevalence were computed through t-test and Chi-square analysis respectively. Significant differences of mean cardiometabolic measures between depressive symptom status groups were also determined by analysis of covariance (adjusted for traditional cardiovascular risk factors and additional factors as specific per manuscript). Multivariate analysis was used to demonstrate associations between left ventricular hypertrophy (LVH) and cardiometabolic markers in Africans with depressive symptoms (Manuscript 1 and 2) and a logistic regression analysis were performed to examine the association between depressive symptoms and inflammatory/haemostatic factors (Manuscript 3). All subjects who participated gave informed consent, the study was approved by the Ethics Committee of North-West University (NWU-0003607S6), in accordance with the principles outlined by the World Medical Association Declaration of Helsinki of 1975 (revised 2008). Results and conclusions of the individual manuscripts - The aim of the study was to investigate the associations between depressive symptoms and cardiometabolic function including cardiovascular dysfunction. Markers of cardiometabolic function assessed were 24 hour blood pressure measurements, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], inflammatory and haemostatic variables (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Manuscript 1, focused on LVH as a marker of cardiovascular dysfunction and metabolic syndrome components as markers of cardiometabolic function. The aim of the study was to assess the associations between LVH and metabolic syndrome (MetS) risk markers in participants with and without depressive symptoms. Results revealed that in African men with depressive symptoms the most significant determinants of LVH were systolic blood pressure (SBP) and the percentage glycosylated haemoglobin (HbA1c). While in African women (with depressive symptoms), this association was determined by low high-density lipoprotein (HDL-cholesterol). The study concluded that in black African men, independent of depressive symptoms, cardiometabolic factors (namely SBP and HbA1c) may be the driving significant factors in the development of cardiovascular diseases. Furthermore, the data showed that depressive symptoms in African women were associated with a measure of target end organ damage, and that this association was driven by a metabolic factor. Manuscript 2, the aim of this manuscript was to examine the relationship between depressive symptoms, neuroendocrine responses [with cortisol and 3-methoxy-phenylglycol (MHPG) as markers] and cardiovascular risk, i.e. LVH. The results revealed that Africans with depressive symptoms demonstrated blunted cortisol and MHPG levels in response to acute mental stress, in comparison to those without symptoms of depression. Additionally, these low cortisol and blunted MHPG responses were associated with LVH in this ethnic group. The conclusion for this manuscript was that, blunted neuroendocrine responses linked depressive symptoms and ECG left ventricular hypertrophy in Africans. When coupled to their hypertensive status, these vasoconstrictive responses (cortisol and MHPG) may underpin the increased long-term depression and vascular disease risk in urban Africans. Manuscript 3, the aim of this manuscript was to investigate the relationship between depressive symptoms and inflammatory/haemostatic markers in a cohort of urban-dwelling black African men and women. Our data demonstrated hypercoagulation vulnerability in African men with depressive symptoms. The African men with signs of depression displayed higher plasminogen activator inhibitor (PAI-1) levels and marginally elevated D-dimer levels. It was concluded that hypercoagulation may partially be the mediating factor between depressive symptoms and cardiovascular risk in African men; a situation that may be exacerbated by hyperkinetic blood pressure. In conclusion, through the assessement of cardiometabolic function and neuroendocrine responses, it seems that Africans withdepressive symptoms are at great risk for cardiovascular related morbidity and mortality, this was particulary evident in the African men (Manuscript 1 and 3). Additionally, it appears that blunted neuroendocrine responses and hypercoagulation could be seen as possible cardiovascular risk markers in Africans with depressive symptoms. / PhD (Physiology), North-West University, Potchefstroom Campus, 2014

Age, male sex, hypertension, smoking, diabetes, dyslipidaemia, and obesity are considered as established risk factors for cardiovascular diseases. Several of these established cardiovascular risk factors are strongly influenced by lifestyle. Novel biomarkers from different mechanistic pathways have been associated with cardiovascular risk, but their clinical utility is still uncertain. The overall objective of the thesis was to evaluate the associations between certain lifestyle factors (physical activity and snuff use), biomarkers reflecting the haemostatic and the inflammatory systems and risk of a future first-ever myocardial infarction.  A prospective incident nested case-control study design was used with a total of 651 cases of myocardial infarction and 2238 matched controls from the population-based Northern Sweden Health and Disease Study.  The effects of commuting activity, occupational and leisure time physical activity on risk of myocardial infarction were studied. A clearly increased risk of myocardial infarction was found for car commuting compared to active commuting (walking, cycling or going by bus). High versus low leisure time physical activity was associated with decreased risk of myocardial infarction. Low occupational physical activity was associated with risk of myocardial infarction in men.  The risk of myocardial infarction or sudden cardiac death was studied in male snuff users compared to non-tobacco users. No increased risk was found for myocardial infarction or sudden cardiac death among snuff users without a previous history of smoking. However, for sudden cardiac death the study did not have statistical power to detect small differences in risk.  Plasma levels of haemostatic markers have previously shown to be associated with risk of myocardial infarction, but as haemostatic markers are also acute-phase reactants, it is not clear if their association with myocardial infarction is independent of inflammatory markers. In the present study, the haemostatic markers D-dimer, von Willebrand factor (VWF), tissue plasminogen activator (t-PA), and tissue plasminogen activator/plasminogen activator inhibitor-1 complex (t-PA/PAI-1 complex) were associated with risk of myocardial infarction after adjustment for established risk factors and the inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6). Furthermore, the addition of eight haemostatic and inflammatory markers could improve the predictive ability for future myocardial infarction beyond that of a model utilizing only established risk factors.  Established risk factors and novel biomarkers were explored as potential mediators of the reduced risk of myocardial infarction related to active commuting. A combination of established risk factors, haemostatic and inflammatory markers appeared to explain a substantial proportion (40%) of the difference in risk for myocardial infarction between active commuters and car commuters. IL-6, t-PA, t-PA/PAI-1 complex, apo B/apo A-1 ratio, and BMI seemed to be the largest potential mediators when tested individually. In conclusion, regular physical activity such as active commuting is associated with reduced risk of a first-ever myocardial infarction. This effect could in part be mediated through a beneficial influence on haemostasis and inflammation, as well as a positive impact on established risk factors. Several haemostatic markers are associated with risk of myocardial infarction independent of established risk factors and inflammatory markers. The combination of haemostatic and inflammatory markers may enhance predictive ability beyond established risk factors. Our findings do not support the hypothesis that snuff use increases the risk of myocardial infarction.